Neutrophils are the first key effector innate immune cells recruited toward inflammatory sites. Through the release of neutrophilic extracellular traps (NETs), the production of reactive oxygen species (ROS), degranulation and phagocytosis, neutrophils play a central role in the rapid elimination of invading pathogens. Recently, increasing attention has been given to the role of neutrophils in chronic inflammation, challenging the dichotomy between innate and adaptive immune responses. In chronic inflammatory conditions, neutrophils generally display a hyperinflammatory phenotype via dysregulated pathogen defense mechanisms. Excessive neutrophil activation may result in aberrant cell death, uncontrolled oxidative burst or NET formation and sustained release of inflammatory mediators such as proteases and inflammatory cytokines. Therefore, neutrophils contribute to the development of a sustained inflammatory environment and cause collateral tissue damage. In addition to their direct inflammatory effects, neutrophils further orchestrate inflammation and tissue remodeling by actively engaging in crosstalk with other cells within the immune microenvironment, such as endothelial cells, monocytes, platelets, and T and B cells. This review summarizes the current knowledge of the emerging role of neutrophils in the context of chronic inflammation. The key characteristics of neutrophils and their interactions with distinct cell types are discussed within the initial part of the review, whereas the second part focuses on their contributions to the pathophysiology of immune-driven diseases, including rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, systemic lupus erythematosus, chronic obstructive pulmonary disease, and fibrotic disorders. Increasing knowledge on neutrophil behavior in the context of chronic inflammation may offer novel insights into disease pathology and, potentially, the identification of novel therapeutic targets.

Despite its considerable morbidity and mortality, paroxysmal nocturnal haemoglobinuria (PNH) is still underdiagnosed. Patients with PNH can suffer from cardiovascular, gastrointestinal, neurological or haematological symptoms and refer to several specialists. The aim of this paper is to review the diagnosis and the management of PNH patients, with the primary focus on identifying high‐risk groups. Additionally, the implementation and prognostic value of the defined high‐risk groups will be commented on and the management of PNH patients is discussed from a Belgian perspective. Finally, based on the available data, recommendations are provided. Eculizumab is a potent C5 complement inhibitor and reduces intravascular haemolysis and thrombosis in PNH patients and improves their quality of life. As thrombosis is the main cause of death in PNH patients, identifying high‐risk PNH patients in need of therapy is essential. Currently, novel complement inhibitors are in development and the first data seem promising. Another challenge in PNH is to identify new markers to assess the thrombotic risk to achieve a better risk‐based prophylactic anti‐thrombotic management. Finally, because of the low prevalence of the disease, PNH patients should be included in the prospective PNH registry, which will offer new insights on the natural course of the disease and the impact of treatment of PNH.

Myeloproliferative neoplasms (MPNs) are uncommon in children/young adults. Here, we present data on unselected patients diagnosed before 25 years of age included from 38 centers in 15 countries. Sequential patients were included. We identified 444 patients, with median follow-up 9.7 years (0-47.8). Forty-nine (11.1%) had a history of thrombosis at diagnosis, 49 new thrombotic events were recorded (1.16% patient per year [pt/y]), perihepatic vein thromboses were most frequent (47.6% venous events), and logistic regression identified JAK2V617F mutation (P = .016) and hyperviscosity symptoms (visual disturbances, dizziness, vertigo, headache) as risk factors (P = .040). New hemorrhagic events occurred in 44 patients (9.9%, 1.04% pt/y). Disease transformation occurred in 48 patients (10.9%, 1.13% pt/y), usually to myelofibrosis (7.5%) with splenomegaly as a novel risk factor for transformation in essential thrombocythemia (ET) (P= .000) in logistical regression. Eight deaths (1.8%) were recorded, 3 after allogeneic stem cell transplantation. Concerning conventional risk scores: International Prognostic Score for Essential Thrombocythemia-Thrombosis and new International Prognostic Score for Essential Thrombocythemia-Thrombosis differentiated ET patients in terms of thrombotic risk. Both scores identified high-risk patients with the same median thrombosis-free survival of 28.5 years. No contemporary scores were able to predict survival for young ET or polycythemia vera patients. Our data represents the largest real-world study of MPN patients age < 25 years at diagnosis. Rates of thrombotic events and transformation were higher than expected compared with the previous literature. Our study provides new and reliable information as a basis for prospective studies, trials, and development of harmonized international guidelines for the specific management of young patients with MPN.

Myelofibrosis (MF) is a clonal myeloproliferative neoplasm, typically associated with disease-related symptoms, splenomegaly, cytopenias and bone marrow fibrosis. Patients experience a significant ... Plain language summary Myelofibrosis (MF) is a rare type of blood cancer that interferes with the process of blood cell production by the bone marrow. In patients with MF, the bone marrow becomes o... Graphical abstract The Phase III MANIFEST-2 Trial Tweetable abstract Read up on the ongoing MANIFEST-2 trial evaluating #pelabresib and ruxolitinib in JAKi treatment-naive patients with #myelofibrosis in this recently published #openaccess article

CML, PV, ET and PMF are so called classical MPN with distinct clinical phenotypes. The discovery of the BCR-ABL1 translocation and mutations in driver genes JAK2, MPL and CALR has provided novel insights in their pathogenesis. While these mutations are thought to be mutually exclusive, rare cases of MPN with coexisting driver mutations have been reported. However, little is known about the clinical, biological and molecular characteristics of these patients and the interaction of the neoplastic clones. We retrospectively studied 11 MPN patients with coexisting driver mutations (JAK2 V617F + BCR-ABL1: n = 8; CALR type 2 + BCR-ABL1: n = 1; JAK2 V617F + MPL W515: n = 1; JAK2 V617F + CALR type 1: n = 1). To assess possible associated molecular aberrations, we analysed DNA of six patients using NGS. In four CML patients, decreasing BCR-ABL1 transcript levels with increasing JAK2 V617F allele burden under TKI were observed. This strongly suggests that the coexistence of driver mutations originates from two different clones growing independently. Additional somatic mutations were detected in 5 out of 6 (83%) patients affecting 4 different genes, confirming the heterogeneity of this study cohort. Suboptimal response to TKI was observed with a higher frequency (4/8 patients) than reported in conventional series of CML and the overall tolerance of treatment with hydroxyurea and/or imatinib in our series was poor. Given the emergence of NGS in clinical practice, more similar cases will be identified in the coming years. The optimal treatment strategy for this rare group of patients is uncertain and toxicity of combination treatment may have to be considered.